This invention relates to the drug, ketorolac and the synthesis of compounds useful in the manufacture of ketorolac. Ketorolac tromethamine is a pharmaceutical compound useful as an analgesic.
U.S. Pat. No. 4,087,539 and U.S. Pat. No. 4,089,969 (Muchowski; Syntex) teach the compound ketorolac and related compounds, and methods for their synthesis based on acetonedicarboxylate chemistry.
U.S. Pat. No. 4,140,698 (Van Horn; Syntex) teaches that 5-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids are prepared by hydrolysis from their corresponding nitrites. It teaches specifically the use of N-hydroxyethylpyrrole in a Mannich Reaction to synthesize a compound that can be useful in the synthesis of ketorolac.
U.S. Pat. No. 4,458,081 (Muchowski; Syntex) teaches that 5-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids are prepared by xcex2-decarboxylation of the corresponding dialkly-1,1-dicarboxylates.
U.S. Pat. No. 5,082,951 (Muchowski; Syntex) teaches that 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates are prepared from 2-aroylpyrroles, and that hydrolysis and mono-decarboxylation of these compounds affords ketorolac and related compounds.
Briefly, the invention comprises several novel compounds useful in the synthesis of ketorolac, as well as methods of synthesizing ketorolac and its precursors.
In this specification and claims, numerical values and ranges are not critical unless otherwise stated. that is, the numerical values and ranges may be read as if they were prefaced with the word xe2x80x9caboutxe2x80x9d or xe2x80x9csubstantiallyxe2x80x9d.
A starting point in the synthesis of the compounds of interest is N-(2-bromoethyl) pyrrole (xe2x80x9cBEPxe2x80x9d). BEP is commercially available in at least small quantities. It can also be easily synthesized by the condensation of 2,5-dimethoxytetrahydrofuran (xe2x80x9c2,5-DMTxe2x80x9d) and bromoethylamine hydrobromide (xe2x80x9cBEA.HBrxe2x80x9d) as shown in reaction I. 
The novel compounds R 4-(N-pyrrolo)-2-cyanobutanoate (xe2x80x9cR-PCBxe2x80x9d) can be produced by the alkylation of the R-cyanoacetate with BEP wherein R is an organic moiety that will not interfere with the subsequent reactions (the R moiety is ultimately removed in the production of ketorolac). Importantly, in this application the symbol xe2x80x9cRxe2x80x9d refers to an attached moiety and should not be interpreted as an indication of the stereochemistry of the molecule. Preferred R moieties include alkyl such as methyl, ethyl, propyl, iso propyl, and butyl, cyclo alkyl such as cyclohexyl, aromatic such as benzyl, and substituted analogs of the forgoing such as chloro or fluoro substituted. Preferred moieties are alkyl, with methyl and ethyl being more preferred and ethyl being most preferred. Thus, the most preferred species is ethyl 4-N-pyrrolo-2-cyanobutanoate (xe2x80x9cEPCBxe2x80x9d). This alkylation reaction preferably takes place in the presence of sodium ethoxide in ethanol at 85xc2x0 C., as shown in reaction II (The sodium ethoxide is a strong base, used to deprotonate the ethyl-cyanoacetate. The resulting carbanion is alkylated by the BEP.) 
The resulting R-PCB (preferably EPCB) is a novel compound that is useful in the synthesis of ketorolac.
R-PCB (EPCB) can be used in a novel synthetic method where it is reacted in a modified Friedel-Crafts acylation with benzoyl chloride, as shown in reaction III, to produce the novel compounds R 4-N-(2xe2x80x2-benzoyl)pyrrolo-2-cyanobutanoate (xe2x80x9cR-BPCBxe2x80x9d), wherein R has the meaning given above. Thus, the preferred species is ethyl 4-N-(2xe2x80x2-benzoyl) pyrrolo-2-cyanobutanoate (xe2x80x9cEBPCBxe2x80x9d). 
In reaction III, it is important that no catalyst be used. While the use of a catalyst is typically standard in an ordinary Friedel-Crafts reaction, in the case of this reaction, the use of a catalyst will cause undesired side reactions (production of polymeric material and unwanted isomers). Mixing and heating the reaction mixture to boiling is also important to help expel HCl byproduct which would act as an undesired catalyst. The temperature is desirably 120 to 180xc2x0 C., preferably 140 to 160xc2x0 C., more preferably 145 to 155xc2x0 C., and ideally 150 to 155xc2x0 C. It has been found that xylenes are an exemplary reaction medium. Xylenes will normally undergo Friedel-Crafts reaction, but in the modified Friedel-Crafts reaction conditions of this invention, the xylenes do not react.
R-BPCB (EBPCB) is useful in a novel reaction in which it is cyclized as shown in reaction IV: 
In reaction IV, R-BPCB (EBPCB) is reacted with a compound of high oxidative potential that is capable of promoting a single electron transfer. By xe2x80x9chigh oxidative potentialxe2x80x9d is meant 1.54 electron volts or greater. Suitable such compounds of high oxidative potential capable of single electron transfer include Ce3+, Mn3+ compounds. An exemplary compound is (CH3C(O)O)3Mn.2H2O. Suitable solvents include EtOH, MeOH and HOAc, with acetic acid being preferred. Similar reactions (see Artis et al., Chem Rev. 1996, 96, p. 352-353) teach the use of temperatures of 20 to 80xc2x0 C., but it has been discovered that novel reaction IV is desirably run at temperatures above 80xc2x0 C., preferably 85 to 118xc2x0 C., more preferably 90 to 100xc2x0 C., and most preferably 92 to 95xc2x0 C.
After cyclization of the R-BPCP, the resulting product ethyl-5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2a] pyrrole-1-carboxamide, 1-carboxylate (structure given below) is easily subjected to hydrolysis with a strong base such as sodium hydroxide, as shown in reaction V-a to yield the novel compound 5a sodium 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxamide-1-carboxylate. 
5-a is easily decarboxylated with a strong acid such as hydrochloric acid, as shown in reaction V-b, to yield the novel compound 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxamide (xe2x80x9cketorolac carboxamidexe2x80x9d). 
The xe2x80x9cketorolac carboxamidexe2x80x9d is in turn easily hydrolyzed by anyone skilled in the art by reacting with first a strong base such as sodium hydroxide and then a strong acid such as hydrochloric acid to convert to the acid, as shown in reaction V-c, to yield 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid (ketorolac free acid). Ketorolac free acid can be formulated directly or can be converted to the tromethamine salt by reaction with tromethamine (H2NC(CH2OH)3) according to known processes. 